The purpose of the proposed research is to expand current understanding of factors which modulate the susceptibility of the kidney to acute ischemic and nephrotoxic injury. To achieve this goal we will test the hypothesis that 4 perturbations characteristic of but not exclusively found in chronic renal disease (high organic anion (OA), high organic cation (OC), high inorganic phosphate (Pi), and high nitrogen (N2) loads per nephron) can increase renal susceptibility to acute renal failure (ARF). The rationale underlying this hypothesis is that patients with chronic renal failure are highly susceptible to ischemic and toxic renal injury. Previous work completed in this laboratory indicate that infusions of OAs, OCs, Pi, and amino acids can exacerbate both nephrotoxic and ischemic ARF. The specific goals of the proposed investigation will be to 1) help define possible transport, cellular, and hemodynamic determinants of these responses, 2) to determine their histopathologic correlates, and 3) to test whether increased nephron loads of these and other "renal failure toxins" induced by reductions in renal mass, rather thnan by exogenous compound infusion, can also exacerbate acute ischemic and toxic renal injury. We will attempt to achieve these goals by studying the effects of OAs, OCs, Pi and N2 loading and progressive renal ablation on 3 experimental models of ARF: renal ischemia and HgCl2 and gentamicin-induced ARF. Cellular energy kinetics will be studied by assaying renal cortical tissues for adenine and pyridine nucleotides and by studying the effects of specific test compounds on in vitro mitochondrial respiration. Using the information derived from these experiments attempts will be made to protect against experimental ARF by 1) improving renal cortical energy kinetics, 2) by inhibiting renal transport of ARF potentiating OAs and OCs, and 3) by dietary Pi and protein restriction. The proposed research has been formulated to contribute to the following long-term objectives: 1) decrease the incidence and severity of ARF by identifying and then abrogating clinical factors that enhance renal susceptibility to injury; and 2) help define pathways through which renal injury are mediated.